Potent Diuretic Research Articles

A study of serum and myocardial digitoxin concentrations in man during cardiac arrest.

In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 (+/- 1.86, range 0.6-8.2) ng/ml, significantly higher (P less than 0.001) than the "eudigitalized" concentration (1.3 +/- 0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ng/ml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 +/- 2.66 v. 1 +/- 0.26 mg/dl for non-toxic subjects, P less than 0.001), partly due to a higher mean daily digoxin dose (0.40 v 0.31 mg/day, P less than 0.05) and frequently associated with potent diuretic therapy (73 v 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (14%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 (+/- 63.3, range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration (r=0.8107, P less than 0.01) or serum creatinine concentration (r=0.4637, P less than 0.001).

Effect of infusion of pharmacologic amounts of vasopressin on renal electrolyte excretion

Aqueous vasopressin was infused to bicarbonate- and glucose-loaded dogs and to nonloaded antidiuretic dogs in doses of 50 mU/kg per min or 50 mU/kg per h. Both doses caused a marked increase in sodium, chloride, and water excretion. The larger dose raised the fractional excretion (sodium clearance (C-Na)/glomerular filtration rate (GFR) times 100) of these ions from 2% or less to in excess of 20%. Blocking the pressor effects of these doses of vasopressin with sodium nitroprusside did not alter the marked natriuretic and chloriuretic effect. The maximal rate of bicarbonate and glucose reabsorption was not depressed by vasopressin infusion; fractional phosphate excretion, however, was markedly increased. Inhibiting distal hydrogen ion secretion by inducing selective aldosterone deficiency failed to uncover a vasopressin-induced inhibition of proximal bicarbonate reabsorption that might have been masked by increased distal bicarbonate reabsorption. There was no significant change in GFR, renal plasma flow, or filtration fraction. The distribution of cortical renal blood flow (measured by the radioactive microsphere technique) shifted toward the inner cortex after vasopressin administration. Vasopressin, in pharmacologic doses, is a potent diuretic that most likely exerts this effect by directly inhibiting sodium reabsorption at a point in the nephron distal to the proximal tubule.

Studies on the syntheses of N-heterocyclic compounds. XXVI. Syntheses of pyrido(3,4-d)pyridazine derivatives. III.

A new synthetic route to 1, 4-dimorpholino-7-phenylpyrido [3, 4-d] pyridazine (1), a potent diuretic, has been investigated. Chlorination and the subsequent dechlorination by catalytic hydrogenation of ethyl 3-cyano-2-oxo-6-phenyl-4 (1H)-pyridinecarboxylate (2) gave ethyl 3-cyano-6-phenyl-4-pyridinecarboxylate (6), which was also obtained by desulfurization of ethyl 3-cyano-6-phenyl-2-thioxo-4 (1H)-pyridinecarboxylate (3). 6 was led to 7-phenylpyrido [3, 4-d] pyridazine-1, 4 (2H, 3H)-dione (12), a key intermediate in the synthesis of 1, by way of cyclic imide (10) or anhydride (11). Several homologs of 1 could also be prepared by employing these procedures. Reactivity of the three chloro groups in 1, 4, 5-trichloro-7-phenylpyrido [3, 4-d] pyridazine (18) towards nucleophilic substitution with morpholine is discussed.

Aminobenzoic acid diuretics. 7. 3-Substituted 4-phenyl-, 4-arylcarbonyl-, and 4-arylmethyl-5-sulfamoylbenzoic acids and related compounds

Various 4-substituted 3-alkylamino-, 3-alkoxy-, 3-alkylthio-, and 3-alkyl-5-sulfamoylbenzoic acids related to known aminobenzoic acid diuretics were synthesized and screened for their diuretic properties in dogs. The tabulated results from a 3-hr test period revealed that generally the diuretic profile and potency could be retained when 3-alkoxy, 3-alkylthio, and 3-phenethyl were substituted for the 3-alkylamino moiety. The high potency of several 3-alkoxy-, 3-alkylthio-, and 3-phenethyl-4-benzoyl-5-sulfamoylbenzoic acids confirmed previous suggestions that the apparent diuretic effect of 4- and 5-alkylamino-6-carboxy-3-phenyl-1,2-benzisothiazole 1,1-dioxides originates from the corresponding 4-benzoyl-5-sulfamoylbenzoic acid derivatives due to an existing equilibrium in plasma. 4-Benzoyl-5-sulfamoyl-3-(3-thenyloxy) benzoic acid (118) is among the most potent benzoic acid diuretics hitherto synthesized and shows significant diuretic activity in dogs at 1 mug/kg. The results obtained with different 3-substituted 4-phenyl-5-sulfamoylbenzoic acids supported the earlier concept regarding the steric influence of the 4-substituent on the diuretic potency of sulfamoylbenzoic acid diuretics.

Studies on the syntheses of N-heterocyclic compounds. XXIII. The photochemical reaction of polyazanaphthalene derivatives.

Photochemical reactions of tetraazanaphthalene derivatives, I, II, and III, with alcohols and cyclic ethers in the presence of photosensitizer resulted in selective addition at the 3, 4 C=N bond to give substituted-3, 4-dihydro derivatives. Potential diuretic activity was shown by many of the obtained compounds.

Changes of glomerular filtration rate and renal plasma flow following intravenous bumetanide in organic heart disease.

Abstract: The renal effects of bumetanide, a new potent diuretic, were studied in ten patients with latent congestive heart failure. Following the intravenous administration of 3 mg bumetanide the glomerular filtration rate (GFR) and renal plasma flow (RPF) showed initial, statistically significant increments over control values, and subsequent statistically significant reductions. This biphasic pattern was unrelated to the diuresis and natriuresis which were sustained for a longer period. The pathophysiological mechanisms involved in the changes of GFR and RPF are discussed and it is suggested that the initial rise in GFR and RPF is primarily due to a vasodilating effect of bumetanide.

Renal concentration of citrate as a negative modulator of diuretic response to mercurials.

IN several mammalian species, including man, the potency of organomercurial diuretics depends on the acid-base status. Acidifying salts (for example, ammonium chloride) markedly enhance the diuretic response to mersalyl1. To account for this, Weiner et al.2 proposed that (a) hydrogen ions facilitate the cleavage of the carbon-mercury bond of organomer-curials and (b) the diuretic response is elicited by the interaction of mercuric ions with renal diuretic receptors. The authors based their conclusions on the excellent correlation between the liberation of mercuric ions from a given organomercurial under acidotic conditions in vitro and its diuretic potency in dogs in vivo. Recently we reported that rapid alkalinisation of urine brought about by treatment of dogs with acetazolamide decreases the diuretic response to inorganic mercury complexed with cysteine3. This observation led us to postulate that alterations in acid-base balance not only modify the rate of cleavage of the carbon-mercury bond in organo-mercurials but also must control the diuretic response to mercuric ions. Our findings are compatible with the following hypothetical chain of events. Alkalosis increases and acidosis decreases the renal concentrations of an endogenous metabolite which is capable of complexing mercury. In the kidneys the partition of mercuric ions between the diuretic receptor and the hypothetical ligand will then depend on the relative concentration of these two substances and their relative affinity for mercury. Specifically, the ratio of mercury bound to these two sites can be described by the following expression where brackets denote the renal concentration, L the hypothetical ligand, R the diuretic receptor, Hg·L and Hg·R the corresponding complexes with mercury, and KHg the effective stability of mercury complexes with the compound denoted in the subscript. A change in any one of the four factors on the right side of the expression will alter the partition of mercury between these two binding sites. If the concentration of the ligand increases in alkalosis, more mercury will be sequestered by the ligand and, as a consequence, a smaller number of mercuric ions would be free to react with renal diuretic receptors. The predicted result will be a decreased diuretic potency of inorganic mercury. Under acidotic conditions when the renal level of the ligand is low, the binding of mercury to the diuretic receptor would not be opposed to the same extent. Therefore the full diuretic response will ensue. The hypothesis does not require that changes in acid-base status alter either the total concentration of mercury in renal tissue or the rate of urinary excretion of mercury. In any case a large fraction of renal mercury is bound to non-specific sulphydryl groups. Many sulphydryl groups of proteins may serve as scavengers for mercury and thus do not participate in the diuretic response1,4.

The sites of action of bumetanide in man

Some pharmacological effects of bumetanide were investigated in 8 healthy volunteers. It was a very potent diuretic, as judged by the fact that, at peak effects during water diuresis, 20% of filtered sodium was excreted in the urine. During water diuresis it reduced free water clearance by approximately 25% and during hydropoenia it reduced the reabsorption of solute free water to a similar extent, indicating a major site of action on the ascending limb of the loop of Henle. A significant phosphaturia was induced during the period of maximum diuresis suggesting an additional action on the proximal tubule. The excretion of urinary titratable acid and ammonium as well as potassium were increased, indicating that the drug did not have a significant effect on sodium transport in the distal tubule. Glomerular filtration rate was not affected but the drug caused a decrease in the renal clearance of uric acid.

2,3-Disubstituted 1,6-naphthyridines as potential diuretic agents.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT2,3-Disubstituted 1,6-naphthyridines as potential diuretic agentsEdward M. Hawes, Dennis K. J. Gorecki, and Dennis D. JohnsonCite this: J. Med. Chem. 1973, 16, 7, 849–853Publication Date (Print):July 1, 1973Publication History Published online1 May 2002Published inissue 1 July 1973https://doi.org/10.1021/jm00265a024RIGHTS & PERMISSIONSArticle Views103Altmetric-Citations18LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (566 KB) Get e-Alerts Get e-Alerts

Mechanism of the acute pressor action of hypokalemia, hypomagnesemia, and hypo-osmolality

The hemodynamic mechanism of the acute pressor action of hypokalemia, hypomagnesemia, and hypo-osmolality was studied in the anesthetized dog. The electrolyte changes were first produced rapidly (within 5 minutes) by a dilutional technique and then more slowly (within 50 minutes) utilizing a potent diuretic and modified Ringer's solution. Blood pressure and cardiac output were measured and total peripheral resistance was calculated. The data suggest that the blood pressure rises because of effects on the periphery when the electrolyte changes are produced rapidly by the dilutional technique and because of effects on both the heart and periphery when the electrolyte changes are produced more slowly by the diuretic technique.

BUMETANIDE, A NEW POTENT DIURETIC

Abstract Bumetanide, a new compound with diuretic action, has been evaluated in 106 patients with congestive heart failure. Bumetanide was found to be a very potent natriuretic and diuretic agent with a rapid onset and a short duration of action. Bumetanide natriuresis was associated with an increased urinary output of potassium and chloride and a trend to development of hypokalemia, hypochloraemia and metabolic alkalosis. Bumetanide was able to decrease renal‐diluting and renal‐concentrating abilities and has apparently a site of action in the ascending limb of the loop of Henle. In comparative short‐term and long‐term studies bumetanide proved to be equipotent with furosemide at one‐fortieth of its molar dosage. On continued daily administration for several months and with supplements of potassium chloride or spironolactone, bumetanide produced effective diuresis with minimal changes in blood chemistry, haematological status or liver function. Like other saluretics it caused a tendency to hyperuricaemia, but it did not provoke gouty arthritis or diabetes mellitus. Bumetanide is very well tolerated and is one of the most potent diuretics available to‐day.

Renal handling and lymph concentration of two cephalosporin analogues, cephacetrile and cephaloridine: an experimental study in dogs.

Cephacetrile (CIBA 36' 278-Ba) and cephaloridine (both cephalosporin derivatives) were compared in dogs with regard to their possible nephrotoxicity, renal handling, and concentration in the renal lymph. No adverse acute effect of either drug on the glomerular filtration rate and effective renal plasma flow was found at very high concentrations in the plasma, with or without concomitant administration of a potent diuretic (furosemide). Cephaloridine was filtered only by the kidney, whereas there was evidence that cephacetrile was also excreted by tubular secretion at low concentrations. The renal lymph concentration of the two antibiotics (in the hilar as well as the capsular lymph vessels) was found to be significantly lower than the simultaneous arterial plasma concentrations. When concentrations in the plasma were high, the relative lymph concentrations of cephaloridine and cephacetrile were in the same range as those of iothalamate (70 to 90% of the arterial plasma level), whereas at low plasma concentrations the lymph concentration of cephacetrile was markedly lower, a finding possibly explained by the active tubular secretion of cephacetrile.

利尿剤に関する研究(第6報)

Activities of various diuretics on experimental nephrotic rats (NER) were compared to those. of normal rats (NWR) with the following results. Spironolactone showed no diuretic activity on NWR but did show a natriuretic effect on NER. Triamterene showed a more potent potassium sparing effect on NER than on NWR and Na+/K+ ratio in the urine was the highest of all diuretics tested. Methyclothiazide showed a most potent diuretic activity on NER and also decreased the excretion of protein and enzymes into the urine of nephrotic animals. Hydrochlorothiazide had a strong chloriuretic effect and decreased proteinuria. Furosemide and Clorexolone had almost the same potent diuretic activity on NER and NWR. Acetazolamide decreased the natriuretic effect and increased the kaliuretic effect on NER. Melarulide showed no diuretic activity but did show an increase of proteinuria on NER. Ethacrynic acid did not have diuretic effects eithers on NER or on NWR. To elucidate the property of diuretics, the experimental rats utilized herein proved adequate.

Pyrido(2,3-d)pyrimidine-6-carboxamides as potential diuretic agents.

Pyrido(2,3-d)pyrimidine-6-carboxamides as potential diuretic agents.

Differential effect of noradrenaline and renal nerve stimulation on vascular resistance in the dog kidney and the release of a prostaglandin E-like substance.

1. The concentrations of prostaglandin E(PGE)- and prostaglandin F(PGF)-like substances in renal venous blood were determined by parallel bioassay of extracts of renal venous effluent before and during adrenergic stimulation of the kidney and were related to simultaneous measurements of renal blood flow and urine flow. 2. When noradrenaline was infused continuously into the renal artery, its initial vasoconstrictor and antidiuretic effects diminished on seven of eight occasions in six dogs. Rapid recovery of renal blood flow and urine flow was invariably associated with increasing concentration in renal venous blood of a substance having the physicochemical, chromatographic and biological properties of a prostaglandin of the E series. In the one instance when rapid early recovery of renal blood flow was not observed the concentration of PGE-like substance was not increased. 3. In contrast, during renal nerve stimulation early rapid recovery of renal blood flow and urine flow did not occur and the concentration of a PGE-like substance in renal venous blood did not increase. The concentration of a PGF-like substance in renal venous effluent did not increase in response to either stimulus. 4. Since PGE2, unlike PGF2α, is a potent renal vasodilator and diuretic, the intrarenal release of this substance by noradrenaline in concentrations similar to those determined for a PGE-like substance (>0·50 ng/ml assayed as PGE2 equivalents) would account for the changes in renal blood flow and urine flow in these experiments when the renal actions of noradrenaline were attenuated. 5. These results support the proposal that renal prostaglandins function in an intrarenal negative feedback control system which regulates antidiuretic and vasoconstrictor systems.

Peritoneal dialysis for intractable heart failure in acute myocardial infarction

This report deals with 4 patients with intractable heart failure following an acute myocardial infarction who evidenced significant immediate benefit from peritoneal dialysis. In 3 patients, loss of edema fluid, abolition of life-threatening arrhythmias, restoration of normal mentation and electrolyte normality, reduction of blood urea nitrogen and return of urinary output were achieved. Before dialysis, increasing doses of digitalis and potent diuretic agents failed to relieve pulmonary edema or reduce venous pressure and oliguria increased.Peritoneal dialysis can be safely and effectively employed during the course of an acute myocardial infarction for intractable congestive heart failure.

Requirement of the adrenal for certain urine electrolyte effects of salmon calcitonin in rats.

SummarySalmon calcitonin, a potent diuretic, natriuretic, phosphaturic agent in the intact rat, was found to be inactive in this regard in the adrenalectomized rat while maintaining full hypocalcemic activity. Pre-treatment of adrenalectomized rats with hydrocortisone alcohol partially restored the natriuretic effect of salmon calcitonin, but did not duplicate effects observed in the intact rat. Other adrenal hormones were independently ineffective in restoring the urine electrolyte effects of salmon CT in the adrenx rat under the experimental conditions utilized.

Ethacrynic acid and furosemide: Diuretic and hemodynamic effects and clinical uses

Ethacrynic acid and furosemide are the most potent diuretic agents currently available. Although the evidence for a proximal tubular site of action is conflicting, the main action of both agents is inhibition of sodium reabsorption along the ascending loop of Henle. Acute administration of ethacrynic acid and furosemide may produce a transient slight increase in both glomerular filtration rate and renal plasma flow, which is followed by a decrease in glomerular filtration rate and renal plasma flow with diuresis and dehydration. In patients who do not have congestive heart failure, acute administration of either drug results in a decrease in plasma volume, central venous pressure and cardiac index, and an increase in arteriovenous oxygen differences. In patients with severe congestive heart failure, plasma volume and central venous pressure fall, but cardiac index increases and arteriovenous oxygen difference narrows. Both drugs have rapid and short duration of diuretic action and wide and steep dose-response curves. Therefore, both drugs can be used in patients with mild to severe congestive heart failure or fluid retention. Both drugs are also effective despite the presence of hypoalbuminemia, acid-base and electrolyte imbalance and a low glomerular filtration rate. Therefore, refractoriness to either agent is unusual in the absence of severe renal failure. Neither drug has been widely used for antihypertensive therapy. No marked difference in antihypertensive potency from that of standard thiazide drugs has been noted. Both drugs are especially useful in those patients with severe hypertension who have concomitant renal failure or congestive heart failure. In this group of patients they help to maintain adequate urinary output and potentiate other antihypertensive drugs. Despite the potent diuretic action of both drugs, side effects are relatively infrequent. However, close monitoring of diuretic response, and acid-base and electrolyte status is recommended.

Diuretic synergy in the treatment of acute experimental cerebral edema.

Acute cerebral edema was created in dogs by the intracarotid injection of sodium lauryl sulfate, a method that produces no structural or vascular disruption in the brain. Cerebrospinal fluid (CSF) pressure elevations were measured through subdural balloons, and ranged from 300 to 1500 mm H2O. The nature of the cerebral edema produced was studied with intravital Trypan blue, electrocorticography, and visual observation of cerebral circulation, and by postmortem histological sections and determinations of brain water content. Two dissimilar diuretic agents were studied: the osmotic diuretic, mannitol; and the renal diuretic, ethacrynic acid. As expected, mannitol reduced CSF pressure effectively, with no significant rebound overshoot. Ethacrynic acid, despite favorable reports, proved to have only a slight effect on CSF pressure but did prove to be a potent diuretic. Unexpectedly, the two agents were found to act synergistically. When both agents were administered, significantly greater reductions in pressure were obtained and pressure reductions were maintained for longer periods.

Electron microscopic study of the inner ear after ethacrynic acid intoxication.

The effects of ethacrynic acid, a potent new diuretic which causes sodium and potassium excretion, on the inner ear were studied by means of phase contrast microscopy and electron microscopy. High doses of ethacrynic acid were administered intra-peritoneally to mice until the Preyer’s reflex disappeared. Some of the animals were sacrificed immediately after final administration of ethacrynic acid and the others were allowed to recover for 1 to 4 months. The drug mainly affected the marginal cells of the stria vascularis. This structural change in the stria vascularis has recovered after 1 to 4 months. The organ of Corti was less affected than the stria vascularis but degeneration appeared in the outer hair cells in the lower turn, starting with degenerations in the mitochondria and distortion of stereocilia which did not recover. In the vestibule, vacuolization and protrusion of the supra-nuclear cytoplasm were observed in both the type I and type II hair cells. The nerve chalice was swollen and its membrane and the cytoplasmic membrane of the type I hair cell were irregularly separated. The ototoxic mechanism of this drug to the inner ear sensory epithelia and the transient hearing loss were discussed from the morphological point of view.